Journal article

Combined BRAF, MEK, and CDK4/6 Inhibition Depletes Intratumoral Immune-Potentiating Myeloid Populations in Melanoma

Emily J Lelliott, Stefano Mangiola, Kelly M Ramsbottom, Magnus Zethoven, Lydia Lim, Peter KH Lau, Amanda J Oliver, Luciano G Martelotto, Laura Kirby, Claire Martin, Riyaben P Patel, Alison Slater, Carleen Cullinane, Anthony T Papenfuss, Nicole M Haynes, Grant A McArthur, Jane Oliaro, Karen E Sheppard

CANCER IMMUNOLOGY RESEARCH | AMER ASSOC CANCER RESEARCH | Published : 2021

Abstract

Combined inhibition of BRAF, MEK, and CDK4/6 is currently under evaluation in clinical trials for patients with melanoma harboring a BRAFV600 mutation. While this triple therapy has potent tumor-intrinsic effects, the impact of this combination on antitumor immunity remains unexplored. Here, using a syngeneic BrafV600ECdkn2a-/-Pten-/- melanoma model, we demonstrated that triple therapy promoted durable tumor control through tumor-intrinsic mechanisms and promoted immunogenic cell death and T-cell infiltration. Despite this, tumors treated with triple therapy were unresponsive to immune checkpoint blockade (ICB). Flow cytometric and single-cell RNA sequencing analyses of tumor-infiltrating im..

View full abstract

Grants

Awarded by National Health and Medical Research Council


Awarded by National Breast Cancer Foundation


Awarded by Peter Mac Postgraduate Scholarship, Melbourne University Research Scholarship


Funding Acknowledgements

This work was supported by National Health and Medical Research Council project grants to G.A. McArthur and K.E. Sheppard (1100189) and J. Oliaro (1139626); a National Breast Cancer Foundation grant to J. Oliaro (IIRS-18-151); Peter Mac Postgraduate Scholarship, Melbourne University Research Scholarship (58616), and Cancer Therapeutics CRC PhD Top Up Scholarship to E.J. Lelliott; and Pfizer Oncology.